In 1896 Andrews became a deacon, and took over the Pembroke College Mission in south London. A year later he was made priest, and became Vice-Principal of Westcott House Theological College in Cambridge.

Andrews had been involved in the Christian Social Union since university, and was interested in exploring the relationship between a commitment to the Gospel and a commitment to justice, through which he was attracted to struggles for justice throughout the British Empire, especially in India.

In 1904 he joined the Cambridge Mission to Delhi and arrived there to teach philosophy at St. Stephen's College, where he grew close to many of his Indian colleagues and students. Increasingly dismayed by the racist behaviour and treatment of Indians by some British officials and civilians, he supported Indian political aspirations, and wrote a letter in the Civil and Military Gazette in 1906 voicing these sentiments. Andrews soon became involved in the activities of the Indian National Congress, and he helped to resolve the 1913 cotton workers' strike in Madras.

Known for his persuasiveness, intellect and moral rectitude, he was asked by senior Indian political leader Gopal Krishna Gokhale to visit South Africa and help the Indian community there to resolve their political disputes with the Government. He met a young Gujarati lawyer, Mohandas Gandhi, who was attempting to organise the Natal Indian Congress and the Indian community to protest against the racial discrimination and police legislation that infringed their civil liberties. Andrews was deeply impressed with Gandhi's knowledge of Christian values and his espousal of the concept of ahimsa, nonviolence - something that Gandhi mixed with inspiration from elements of Christian anarchism. He helped Gandhi to organise an Ashram in Natal and publish his famous magazine, The Indian Opinion.

Following the advice of several Indian Congress leaders and of Principal Susil Kumar Rudra, of St. Stephen's College, Andrews was instrumental in persuading Gandhi to return to India with him in 1915.

In 1918 Andrews disagreed with Gandhi's attempts to recruit combatants for World War I, believing that this was inconsistent with their views on nonviolence. In Mahatma Gandhi's Ideas Andrews wrote about Gandhi's recruitment campaign: "Personally I have never been able to reconcile this with his own conduct in other respects, and it is one of the points where I have found myself in painful disagreement."[2]

Andrews was elected President of the All India Trade Union in 1925 and 1927.

Once C.F. Andrews, along with Rabindranath Tagore, visited Sree Narayana Guru, a spiritual leader from Kerala, South India. Then he wrote to Romain Rolland; that I have seen our Christ walking on the shore of arabian sea in the attire of a hindu sanyasin .[citation needed]

He accompanied Gandhi to the second Round Table Conference in London, helping him to negotiate with the British government on matters of Indian autonomy and devolution.

When the news reached India, through the writings of Christian missionaries J.W. Burton, Hannah Dudley, and R. Piper and a returned indentured labourer, Totaram Sanadhya, of the mistreatment of Indian indentured labourers in Fiji, the Indian Government in September 1915 sent Andrews and W.W. Pearson to make inquiries. The two visited numerous plantations and interviewed indentured labourers, overseers and Government officials and on their return to India also interviewed returned labourers. In their "Report on Indentured Labour in Fiji" Andrews and Pearson highlighted the ills of the indenture system; which led to the end of further transportation of Indian labour to the British colonies. In 1917 Andrews made a second visit to Fiji, and although he reported some improvements, was still appalled at the moral degradation of indentured labourers. He called for an immediate end to indenture; and the system of Indian indentured labour was formally abolished in 1920.

In 1936, while on a visit to Australia and New Zealand, Andrews was invited to and visited Fiji again. The ex-indentured labourers and their descendants wanted him to help them overcome a new type of 'slavery', by which they were bound to the Colonial Sugar Refining Company, which controlled all aspects of their lives. Andrews, however, was delighted with the improvements in conditions since his last visit, and asked Fiji Indians to "remember that Fiji belonged to the Fijians and they were there as guests."

About this time Gandhi reasoned with Andrews that it was probably best for sympathetic Britons like himself to leave the freedom struggle to Indians. So from 1935 onwards Andrews began to spend more time in Britain, teaching young people all over the country about Christ’s call to radical discipleship. Gandhi's affectionate nickname for Andrews was Christ’s Faithful Apostle, based on the initials of his name, "C.F.A". He was widely known as Gandhi's closest friend and was perhaps the only major figure to address Gandhi by his first name, Mohan.[3]